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J. Biol. Chem., Vol. 278, Issue 33, 30732-30740, August 15, 2003

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Maturation and Release of Interleukin-1 by Lipopolysaccharide-primed Mouse Schwann Cells Require the Stimulation of P2X₇ Receptors^*

Aurore Colomar , Vincent Marty, Chantal Médina, Chantal Combe, Patricia Parnet and Thierry Amédée 

From the Laboratoire de Neurobiologie Intégrative, Institut National de la Santé et de la Recherche Médicale U394, Institut François Magendie, Rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France and the Département de Physiologie, Centre de Recherches en Sciences Neurologiques, Université de Montréal, Montréal H3C 3J7, Canada

The P2X₇ receptor, mainly expressed by immune cells, is a ionotropic receptor activated by high concentration of extracellular ATP. It is involved in several processes relevant to immunomodulation and inflammation. Among these processes, the production of extracellular interleukin-1 (IL-1), a pro-inflammatory cytokine, plays a major role in the activation of the cytokine network. We have investigated the role of P2X₇ receptor and of an associated calcium-activated potassium conductance (BK channels) in IL-1 maturation and releasing processes by Schwann cells. Lipopolysaccharide-primed Schwann cells synthesized large amounts of pro-IL-1 but did not release detectable amounts of pro or mature IL-1. ATP on its own had no effect on the synthesis of pro-IL-1, but a co-treatment with lipopolysaccharide and ATP led to the maturation and the release of IL-1 by Schwann cells. Both mechanisms were blocked by oxidized ATP. IL-1-converting enzyme (ICE), the caspase responsible for the maturation of pro-IL-1 in IL-1, was activated by P2X₇ receptor stimulation. The specific inhibition of ICE by the caspase inhibitor Ac-Tyr-Val-Ala-Asp-aldehyde blocked the maturation of IL-1. In searching for a link between the P2X₇ receptor and the activation of ICE, we found that enhancing potassium efflux from Schwann cells upregulated the production of IL-1, while strongly reducing potassium efflux led to opposite effects. Blocking BK channels actually modulated IL-1 release. Taken together, these results show that P2X₇ receptor stimulation and associated BK channels, through the activation of ICE, leads to the maturation and the release of IL-1 by immune-challenged Schwann cells.

Received for publication, April 30, 2003 , and in revised form, June 4, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 33557573709; Fax: 33556989029; E-mail: thierry.amedee{at}bordeaux.inserm.fr.

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